The objective of this research is to identify the mechanisms of total body clearance of volatile halogenated anesthetics and their metabolites in man. By measuring the absorbed dose of drug during clinical anesthesia and the amount exhaled and excreted as urinary metabolites, we have shown that the larger the fraction of dose excreted as urinary metabolites, the larger the fraction which cannot be accounted for by these methods. We propose to extend these balance studies to include halothane and aliflurane, a promising new drug that is resistant to biotransformation. The influence of chronic ingestion of anticonvulsant drugs on the uptake, elimination and extent of biotransformation of halothane and enflurane will be determined. Rates of biotransformation of halothane in man during anesthesia will be assayed by simultaneous measurement of uptake of an anesthetic drug which is resistant to biotransformation. The effects of halothane anesthesia and surgical operation on plasma clearance of antipyrine will be measured. We also plan to determine the extent of irreversible binding of fluorine metabolites in animal and human tissues by a rapid microdialysis method and to measure the rate of clearance of bound metabolites from the tissues. The susceptibility to cleavage of the ether bond of (C14) enflurane will be tested in vivo in the rat.